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2018-03-16 09:38:15 作者: 来源:药事纵横 文字大小:[][][]
FDA于2018年01月18日发布了Establishing Impurity Acceptance Criteria As Part of Specifications for NDAs, ANDAs, and BLAs Based on Clinical Relevance指导原则,药事纵横翻译团队对其进行了翻译,分享给大家。


This MAPP provides guiding principles and approaches for establishing drug substance and drug product impurity1 acceptance criteria for non-mutagenic impurities in new drug applications(NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), based on the consideration of clinical relevance.2


While ICHQ3A(R2) and Q3B(R2)3 apply to new molecular entities produced by chemical synthesis, the principles of these guidances and the principles of this MAPP may apply to other drug substances and drug products, including some semi-synthetic and fermentation products, and synthetic peptides4,submitted in NDAs and ANDAs.

虽然ICH Q3A(R2)和Q3B(R2)[3]适用于化学合成的新型分子实体,但这些指导原则和MAPP中的原则可能也适用于其他原料药和制剂,包括在NDA和ANDA中递交的一些半合成产品、发酵产品及合成多肽类[4]。

The principles in this MAPP may also be used to establish acceptance criteria for DNA-reactive (i.e., mutagenic) impurities that are generally controlled at tighter limits according to the ICH M75.

根据ICH M7[5]对于DNA活性(即致突变性)的杂质一般控制更严格的限度,该MAPP的原则也适用于建立这类杂质的接受标准。

The principles in this MAPP may also apply to investigational drug substances and drug products, depending on the risk.


Where the active ingredient is a single enantiomer, the principles in this MAPP may alsoapply to associated enantiomeric impurities.


Please note that the principles that guide the development of a specification can be impacted by the assessment of risk to safety and efficacy based on context of use as well as other factors, such as clinical experience. The context of use includes, but is not limited to, dosage forms, dosing regimens, route and duration of drug administration, clinical indications, and the intended patient populations (e.g., pediatric or geriatric populations). Therefore, an impurity acceptance criterion cannot be established by one definitive approach and instead needs to be established on a case-by-case basis.



The following are excluded from this MAPP:


s Residual solvents and elemental impurities, as these are adequately addressed in ICH Q3C and ICH Q3D. Refer to ICH Q3C and ICH Q3D for establishing limits for these impurities.

残留溶剂和元素杂质,这些在ICH Q3C和ICH Q3D中进行了充分的说明。参见ICHQ3C和ICH Q3D建立这些杂质的限度。

s Extraneous contaminants that should not occur in drug substances and drug products, and are appropriately addressed by Good Manufacturing Practices(e.g., adventitious viral, bacterial, and mycoplasma contamination).


s Microbiological attributes (e.g., endotoxin, microbial limits).


s Leachables from the container closure system6.


s Polymorphic forms7.


Background 背景

To provide assurance that a product performs as is intended, there is a need to establish impurity acceptance criteria. Currently, the establishment of a drug substance and drug product impurity acceptance criterion can be supported by clinical data, nonclinical data (e.g., in silico, in vitro, and animal data),comparative impurity analysis of the proposed drug product with an FDA approved drug product (listed drug or reference listed drug (RLD)), analytical precision of the method used to measure the impurity, and manufacturing process capability. The intent of this MAPP is to clarify the types of data and information needed as well as the limitations when establishing impurity acceptance criteria. In general, the types of data and information should be guided by the consideration of clinical impact of impurity levels, as opposed to manufacturing process capability, to ensure the acceptance criteria are clinically relevant.


Policy 政策

The terminology described in ICH Q3A(R2), Q3B(R2), and Q6A shouldgenerally be applied to NDA and ANDA products. Specifically, a specification should include the following, where “specified impurity” is any impurity present at greater than the identification threshold:
ICH Q3A(R2)、Q3B(R2)和Q6A中描述的术语一般应适用于NDA和ANDA产品。具体而言,规范应包括以下内容,其中“特定杂质”是指任何超过鉴定阈值的杂质。

Drug Substance 原料药

s   Each specified identified impurity


s   Each specified unidentified impurity


s   Any unspecified impurity with an acceptance criterion of not morethan (≤) the identification threshold


s   Total impurities


Drug Product 制剂

s   Each specified identified degradation product


s   Each specified unidentified degradation product

s   Any unspecified degradation product with an acceptance criterion ofnot more than (≤) the identification threshold


s   Total degradation products


2. For products submitted in NDAs and ANDAs where the applicant’s proposed acceptance criteria are not more than the ICH Q3A(R2) or Q3B(R2) qualification threshold, an acceptable limit for a specified impurity in the drug substance and drug product can be proposed and established at the qualification threshold, provided there are no toxicological, immunological, orclinical concerns at this level. For impurities known to be unusually potent, toxic, or have immunological, pharmacological, or clinical concerns, the proposed acceptance criteria based solely on ICH Q3A(R2) and Q3B(R2) qualification threshold are not sufficient and need to be adequately justified.

在NDA和ANDA递交的产品中,申请人提出了接受标准不超过ICH Q3A(R2)或Q3B(R2)界定阈值,对于原料药和制剂中特定杂质的接受限度可以建立界定阈值,并提供在这个水平没有毒性,免疫或临床相关问题。对于已知杂质异常特性,有毒或具有免疫学,药理学或临床问题的杂质,推荐的接受标准仅仅基于ICH Q3A(R2)和Q3B(R2)的界定阈值是不够的,需要有充分的理由。

2.1  The acceptance criterion for total impurities excluding significant human metabolites8, generally, should not exceed the summation of acceptance criteria forindividual specified (identified and unidentified) impurities. Acceptance criterion for individual impurities that are also significant human metabolites should be considered separately. The sum total of all impurity limits,including those for significant metabolites, should not exceed thresholds thatmay compromise product potency/assay through product expiry.



3.      The proposed acceptance criteria should be justified for thefollowing:对于下面拟定的接受标准应说明是合理的:

Products submitted in NDAs and ANDAs where the applicant’s proposed acceptance criteria are greater than ICH Q3A(R2) or Q3B(R2) qualification threshold.

在NDA和ANDA递交的产品中,申请人提出的接受标准大于ICH Q3A(R2)或Q3B(R2)的界定阈值。

(b) Products submitted in NDAs and ANDAs that are excluded from ICHQ3A(R2) and Q3B(R2)9.


(c) Products submitted in BLAs9.


For impurities listed in a specification, the acceptance criteria should be informed by data derived from clinical trials, nonclinical studies(e.g., in silico modeling, in vitro, and animal studies), context of use, prior knowledge, publicly available information10,and analytical capability, as appropriate.


4. For some products, such as certain biotechnology and complex products, there may be impurities for which the relationship to stability, potency, or potential adverse clinical effects is not clear. This may be either because the analytical techniques available have not allowed thorough characterization of the impurity, or because data regarding the impact of the impurity on clinical performance are lacking. For instance:


s   There may be a high level of uncertainty regarding the clinical impact of an impurity, such as a peptide- orprotein-related impurity.


s   An impurity could be a surrogate for other impurities that might be clinically relevant or for which there is increased uncertainty. For example, for toxin-conjugated drug products, asurrogate may be free protein, fragmented protein, or free toxin, and used to represent the appearance or clearance of other dissociated parts of thetoxin-conjugated product.


In these scenarios, the control strategy, including impurity acceptance criteria, should include greater consideration for manufacturing process capability.


5.  While establishment of impurity acceptance criteria should be guided by the totality of the data and consideration of the clinical impact of impurity levels instead of basing the impurity limits solely on the manufacturing process capability, the manufacturing process consistency shouldbe monitored during the production of the drug substance and the drug productas part of the quality system.


6. Office of Biotechnology Products (OBP) immunogenicity reviewers willuse the existing review process and the principles outlined in the FDA guidance for industry Immunogenicity Assessment for Therapeutic Protein Products toassess the immunogenicity risk of a given impurity for implementing this MAPP.


7.  Other review disciplines (e.g., pharmacology/toxicology (pharm/tox)and clinical) will use existing review processes for implementing this MAPP.

Responsibilities 责任

Responsibilities of the review teams in OPQ: Product quality reviewers will discuss or consult with pharm/tox and/or computational toxicology, clinical, and clinical pharmacology review disciplines, asappropriate, when assessing the potential risk of a given impurity or impurities. Assessments or consults should be initiated as early as possible to allow sufficient time for adequate review. Product quality reviewers should identify relevant information in an application before requesting a consult.



1. NDAs and ANDAs: Acceptance Criterion Not More Than the Qualification Threshold


1.1    a specified impurity with a proposed acceptance criterion not more than the qualification threshold, absent other information to support the need for a lower limit, a proposed acceptance criterion up to the ICH Q3A(R2) orQ3B(R2) qualification threshold is generally acceptable.

对于特定杂质拟定的接受标准不大于界定阈值,缺少其他信息来支持更低的限度,则一般达到ICH Q3A(R2)或Q3B(R2)界定阈值的标准是可以接受的。

1.2 Product quality reviewers should perform due diligence in evaluating impurities and the applicability of ICH threshold levels. This evaluation maybe based on a review of the applicant’s submitted safety rationale, previous FDA experience with identical impurities within CDER-regulated products considering the context of use, or information identified from the published literature. Establishing impurities acceptance criteria at the ICH Q3A(R2) andQ3B(R2) qualification thresholds may not apply if any the following are true:

产品质量评审员应该在评估杂质和ICH阈值水平的适用性方面进行尽职调查。此评估可基于对申请人提交的安全原理的审查,以前的FDA考虑到使用环境的CDER管制产品中的相同杂质的经验,或从公开文献中得到鉴定的信息。如果以下情况属实,依据ICH Q3A(R2)和Q3B(R2)认证阈值内建立杂质接受标准可能不适用。

1.2.1       There are known safety data for the impurities based on their structural class (e.g., impurities known to be DNA reactive (i.e., mutagenic) or the presence of a structural alert formutagenicity).


1.2.2       There is information suggesting that impurities of this class have unusually potent toxicities.


1.2.3       There are compendial limits related to safety which are lower than the ICH qualification thresholds for theimpurities11.

有药典规定与安全性相关的低于ICH界定的杂质限度 [11]。

1.2.4       There are any immunological orother clinical concerns (e.g., pharmacokinetics/pharmacodynamics (PK/PD) activity, target population). 


1.3    If the above information suggests a concern with the proposed impurity level, then assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review:


1.3.1       For toxicology relatedconcerns, the product quality reviewer should request a pharm/tox evaluation toassess the risk to patients for impurities at a specified level.


1.3.2       For immunological or otherclinical concerns, the appropriate immunogenicity, clinical, and clinical pharmacology reviewers should be involved to assess the risk/benefit topatients. A consult should be issued if they are not already part of the assigned review team.


2. NDAs and ANDAs: Acceptance Criterion Greater Than the QualificationThreshold


2.1    For a specified impurity with a proposed acceptance criterion greater than the qualification threshold, data from clinical trials,nonclinical (i.e., in silico, in vitro, and animal) studies, prior knowledge,and publicly available information, including those on significant human metabolites provided by the applicant, should be used by the review disciplines, as appropriate, to assess the adequacy of the proposed acceptance criterion. Assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review. In general, the product quality reviewer should consult with the appropriate pharm/tox, clinical,and/or clinical pharmacology reviewers to conduct the following assessments insupport of the proposed impurity level:


2.1.1       A pharm/tox assessment orconsult for toxicology-related concerns to verify that impurities have been adequately evaluated and the levels of impurities are considered qualified innonclinical studies and/or clinical trials.


2.1.2       Immunogenicity, clinical, and clinical pharmacology assessments or consults, as appropriate, for immunological or other clinical concerns to assess the risk/benefit topatients.


2.2   In addition, the followingshould be considered in the assessment:


2.2.1       The proposed acceptance criterion may be supported by the data demonstrating that the impurity is asignificant metabolite. Whether a metabolite is clinically significant shouldbe the subject of pharm/tox and/or clinical pharmacology consults.


2.2.2       The proposed acceptance criterion for an ANDA or a 505(b)(2) NDA product may be supported by aside-by-side comparative impurity analysis for the proposed product and thelisted drug or RLD using the same analytical method that is shown to besuitable for its intended purpose. The comparative analysis is preferably to beconducted on multiple batches of the proposed product and the RLD. To support proposed new impurities or higher impurity levels than that of the RLD, theapplicant should submit a justification including a risk assessment (seesection 3.2 below on risk assessment).


2.2.3       For those products that have USP monographs12 or other compendial monographs13and the monograph acceptance criteria are greater than the ICH Q3A(R2) orQ3B(R2) qualification thresholds, the monograph limits may be used only if thelimit is justified in an FDA-approved product.


3. BLAs and NDAs/ANDAs Excluded from ICH Q3A(R2) and Q3B(R2)

ICH Q3A(R2)和Q3B(R2)中排除的BLAs和NDAs / ANDAs

3.1    For those chemical drug substances and drug products (a) where monographs apply or (b) that are ANDA and 505(b)(2) NDA products (e.g.,peptides and fermentation products) and are not transitioning to BLA under the Biologics Price Competition and Innovation Act of 2009, recommendation soutlined in the above sections 2.1 and 2.2 should be followed.


3.2    For all other products, such as biologics, a determination of the acceptability of the proposed acceptance criteria of impurities supported by arisk assessment should be made by the product quality reviewer in consultation with other review disciplines including clinical, pharm/tox, immunogenicity, and clinical pharmacology, as appropriate. Assessments or consults should be initiated early during the review cycle to allow sufficient time for adequate review.


3.2.1       A risk assessment will generally consider the impact of an impurity on activity, PK/PD, safety, and immunogenicity.


3.2.2       A risk assessment can includeclinical data, nonclinical data (e.g., in vitro data and animal data), priorknowledge, and publicly available information.


3.2.3       In some cases, uncertainty should be factored into the risk assessment. Uncertainty can be associated with the strength of the data to understand the clinical effect of an impurity aswell as analytical capability and analytics performance to identify and characterize the impurity. Principles laid out in the ICH Q914 and in an FDA scientificpublication15 describing how to manage the uncertainty with respect to the impact of product quality attributes on safety and/or efficacy may be followed.

在某些情况下,风险评估应考虑到不确定因素。不确定性可能与数据的强度有关,以了解杂质的临床效应以及分析能力和分析性能以鉴定和表征杂质。ICH Q9[14]中规定的原则和FDA的科学出版物[15]描述如何管理产品质量属性对安全性和/或功效的影响方面的不确定性。

3.2.4       For immunological concerns regarding products not reviewed by OBP, an immunogenicity consult may be requested from OBP to assess the immunogenicity risk of the impurities. The clinical reviewer on the review team will also evaluate the risk to patients.


3.2.5       For toxicology-relatedconcerns, a pharm/tox assessment or consult should be made to verify that impurities have been adequately evaluated in nonclinical studies and/or clinical trials to assess the risk to patients for impurities at a specified level.

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